Discovery of a Class of Diketopiperazines as Antiprion Compounds
Discovery of a Class of Diketopiperazines as Antiprion Compounds
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DOI：
10.1002/cmdc.201000133
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发表时间：
2010-07-01
期刊：
影响因子：
3.4
通讯作者：
Legname, Giuseppe
中科院分区：
文献类型：
--
作者：
Bolognesi, Maria Laura;Tran, Hoang Ngoc Ai;Legname, Giuseppe
朊病毒疾病是致命的神经退行性疾病和感染性疾病，目前尚无有效的药物治疗手段。这一尚未解决的挑战和最近提出的朊病毒疾病和阿尔茨海默病之间的相互作用，导致了对新的抗朊病毒药物的更迫切的需求。在此，我们报告了一种新的双功能二酮哌嗪（DKP）衍生物1 d，它表现出在低微摩尔范围内对朊病毒在ScGT 1细胞中复制的活性，同时显示出低细胞毒性的鉴定。适当解决的分子建模研究的支持下，我们假设，平面构象是这类化合物的活性的主要决定因素。此外，旨在评估分子水平上的作用机制的研究表明，1 d可能直接与重组朊蛋白（recPrP）相互作用，以防止其转化为致病性错误折叠朊蛋白（PrPSc）样形式。这项研究表明，DKP为基础的抗朊病毒化合物可以作为一个有前途的领导支架在开发新的药物，以打击朊病毒疾病。
Prion diseases are fatal neurodegenerative and infectious disorders for which effective pharmacological tools are not yet available. This unmet challenge and the recently proposed interplay between prion diseases and Alzheimer's have led to a more urgent demand for new antiprion agents. Herein, we report the identification of a novel bifunctional diketopiperazine (DKP) derivative 1 d, which exhibits activity in the low micromolar range against prion replication in ScGT1 cells, while showing low cytotoxicity. Supported by properly addressed molecular modeling studies, we hypothesized that a planar conformation is the major determinant for activity in this class of compounds. Moreover, studies aimed at assessing the mechanism-of-action at the molecular level showed that 1 d might interact directly with recombinant prion protein (recPrP) to prevent its conversion to the pathogenic misfolded prion protein (PrPSc)-like form. This investigation suggests that DKP based antiprion compounds can serve as a promising lead scaffold in developing new drugs to combat prion diseases.